Valgancyclovir hydrochloride (formula 1) or L-valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxypropyl ester hydrochloride, is presently available as a mixture of two diastereoisomers substantially in the same amount.

Valgancyclovir hydrochloride is known from EP 694547 as an antiviral agent particularly against cytomegalovirus infections.
Processes for the preparation of valgancyclovir hydrochloride are also known from U.S. Pat. No. 5,840,890, U.S. Pat. No. 5,856,481 and U.S. Pat. No. 6,083,953. The process disclosed in said patents substantially follows the synthetic path outlined in Scheme 1.

wherein P1, P2 and P3 are well known protecting groups such as those used typically for the synthesis of peptides or, for instance, in the synthesis of Valacyclovir (EP 308 065), or other valine derivatives of gancyclovir (U.S. Pat. No. 5,043,339), e.g. trityl, acetoxy, tert-butoxycarbonyl (BOC), 9-fluorenylmethoxycarbonyl (FMOC), carbobenzoyloxy (Cbz) derivatives and the like.
This synthetic pathway is cumbersome, starting from a substrate with different reactive groups, i.e. hydroxy and amino groups, so that a good selectivity is required in the reaction steps. As described above, this problem is solved by means of protecting groups. In fact, the synthesis starts from a suitably mono-protected derivative of Gancyclovir (2), that is reacted with a suitably protected L-valine, to give compound 3. The hydroxy group protection is then removed by mild hydrolysis and eventually the valine amino protecting group is removed. Optionally, also a P3 protecting group may be present and is removed by an additional step. Overall, of the three (or four, when a P3 group is present) steps needed for preparing valgancyclovir hydrochloride, as shown in scheme 1, two (or three) are deprotection steps.
All these protection-deprotection sequences are of course disadvantageous and affect yields, purity of the compound and costs.
Attempts starting from an unprotected gancyclovir, reported in U.S. Pat. No. 5,700,936, result in a double addition of the L-valine moiety. Hydrolysis of one of the two valine residues affords the desired compound. This approach however yields a mixture of mono-, diesters and gancyclovir, as the hydrolysis is poorly selective. In the same area, but with a different approach, WO 2005/092891 discloses the preparation of valgancyclovir hydrochloride aiming at the selective monoacylation of gancyclovir, but this resulted again in a mixture of mono- and di-esters, plus non-reacted starting material (gancyclovir). The presence of complex mixtures requires extensive additional purifications steps and crystallizations, negatively affecting yields and operability of the process.
Also, attempts to use alternate activated valine derivatives, such as cyclic anhydride of formula 6, were also described in U.S. Pat. No. 5,700,936, U.S. Pat. No. 5,756,73 and U.S. Pat. No. 6,040,446.

However, this approach did not result in an increase of synthetic efficiency, since the compound of formula 6 still needs the presence of the protecting group P2 and requires anyway an additional deprotection step. In addition, the protection P2 in compounds of formula 6 may only refer to N-monosubstituted protecting groups, limiting the flexibility of the process.
It would be therefore useful to avoid such protection-deprotection sequences in order to increase the overall synthetic efficiency. To this purpose, a convenient starting material should have the following advantages:                1 selective vs. other reactive groups present in the compound.        2. able to act as an unprotected L-valine equivalent so as to reduce the number of steps for the preparation of valgancyclovir.        3. commercially available, inexpensive, easy to recover and recycle without further manipulations.        
In fact, in addition to the drawbacks mentioned above, the cleavage of the protecting groups usually involves the transformation of the protecting group itself, that therefore cannot be recycled giving impurities and by-products.
The solution to said problems is not easy since there is only a limited choice of compounds potentially meeting the above criteria. Schiff bases could be considered but they are known to be unstable in even mild acidic conditions, needed for the synthesis of the free acids, that are instead required for the reaction of an adduct of L-valine with the alcohol of formula 2 in the presence of a condensing agent. It has been reported by Halpern, B. et al. Aust. J. Chem, 1974, 27, 2047, and in Aust. J. Chem. 1976, 29, 1591, that ketones of formula 10, give adducts sufficiently stable to yield the free acid derivatives. Such adducts, however, react with amino groups, whereas their reaction with aliphatic alcohols has not been disclosed. In addition, compound 2 is hindered, sparingly soluble, and poorly reactive so that the hindrance of the obtained adduct itself makes it even less reactive.